Genetic disorders that produce neuronal ectopias can result in the development of epilepsy or, in extreme cases, severe mental retardation. Our lab studies the molecular controls of neuronal migration with the goal of understanding the events that are required to orchestrate the appropriate formation and function of the nervous system. Understanding of the mechanisms regulating neuronal migration has been facilitated by studies on mouse mutants that have neuronal positioning defects. Analyses of the defective genes in these mice have led to insights about the mechanisms regulating neuronal migration. This lab focuses on the products of four genes that work together on a common signaling pathway to regulate neuronal placement. These proteins include the secreted protein, Reelin, that acts through the cell surface receptors ApoER2 and VLDLR to induce the tyrosine phosphorylation of a cytoplasmic protein Dab1. The Dab1 tyrosine phosphorylation sites that are regulated by this cascade have been shown genetically to be required for Dab1 function and normal brain development. We have therefore concentrated our efforts on identifying and characterizing proteins that interact with Dab1 in a tyrosine phosphorylation dependent manner. Recently, we have identified Nck beta as one such protein. In cultured fibroblasts, we have demonstrated that co-overexpression of Dab1 and Nck beta leads to alterations in the actin cytoskeleton. In response to Reelin stimulation, Nck beta translocates from the cell soma into cellular processes where it may act to regulate cytoskeletal dynamics. We are currently analyzing other Dab1 binding proteins to determine if they are regulated by Reelin signaling. The components of this pathway continue to be expressed in adult animals. Therefore, in addition to analyzing a role for this cascade in the formation of the brain, we are also investigating a role for this signaling cascade in the maintenance of nervous system function. This is being investigated using a conditional allele for Dab1, which shall be inactivated in a subset of neurons postnatally.